Increase In Plasma Free Fatty Acid Concentration Research Articles

Distinct Mechanisms Responsible for the Increase in Glucose Production and Ketone Formation Caused by Empagliflozin in T2DM Patients.

To examine the mechanisms responsible for the increase in glucose and ketone production caused by empagliflozin in patients with type 2 diabetes mellitus (T2DM). Twelve subjects with T2DM participated in two studies performed in random order. In study 1, endogenous glucose production (EGP) was measured with 8-h infusion of 6,6,D2-glucose. Three hours after the start of 6,6,D2-glucose infusion, subjects ingested 25 mg empagliflozin (n = 8) or placebo (n = 4), and norepinephrine (NE) turnover was measured before and after empagliflozin ingestion with 3H-NE infusion. Study 2 was similar to study 1 but performed under pancreatic clamp conditions. When empagliflozin was ingested under fasting conditions, EGP increased by 31% in association with a decrease in plasma glucose (-34 mg/dL) and insulin (-52%) concentrations and increases in plasma glucagon (+19%), free fatty acid (FFA) (+29%), and β-hydroxybutyrate (+48%) concentrations. When empagliflozin was ingested under pancreatic clamp conditions, plasma insulin and glucagon concentrations remained unchanged, and the increase in plasma FFA and ketone concentrations was completely blocked, while the increase in EGP persisted. Total-body NE turnover rate was greater in subjects receiving empagliflozin (+67%) compared with placebo under both fasting and pancreatic clamp conditions. No difference in plasma NE concentration was observed in either study. The decrease in plasma insulin and increase in plasma glucagon concentration caused by empagliflozin is responsible for the increase in plasma FFA concentration and ketone production. The increase in EGP caused by empagliflozin is independent of the change in plasma insulin or glucagon concentrations and is likely explained by the increase in NE turnover.

Plasma free fatty acid concentration is closely tied to whole body peak fat oxidation rate during repeated exercise

Plasma free fatty acids (FFA) are a major contributor to whole body fat oxidation during exercise. However, the extent to which manipulating plasma FFA concentrations will influence whole body peak fat oxidation rate (PFO) during exercise remains elusive. In this study we aimed to increase plasma FFA concentrations through a combination of fasting and repeated exercise bouts. We hypothesized that an increase in plasma FFA concentration would increase PFO in a dose-dependent manner. Ten healthy young (31 ± 6 yr) (mean ± SD) well-trained (maximal oxygen uptake 65.9 ± 6.1 ml·min-1·kg-1) men performed four graded exercise tests (GXTs) on 1 day. The GXTs were interspersed by 4 h of bed rest. This was conducted either in a fasted state or with the consumption of a standardized carbohydrate-rich meal 3.5 h before each GXT. Fasting and previous GXTs resulted in a gradual increase in PFO from 0.63 ± 0.18 g/min after an overnight fast (10 h) to 0.93 ± 0.17 g/min after ∼22 h of fasting and three previous GXTs. This increase in PFO coincided with an increase in plasma FFA concentrations (r2 = 0.73, P < 0.0001). Ingestion of a carbohydrate-rich meal 3.5 h before each GXT resulted in unaltered PFO. This was also reflected in unchanged plasma FFA, glucose, and insulin concentrations. In this study we show that plasma FFA availability is closely tied to whole body PFO and that the length of fasting combined with previous exercise are robust stimuli toward increasing plasma FFA concentration, highlighting the importance for preexercise standardization when conducting GXTs measuring substrate oxidation. NEW & NOTEWORTHY We show that peak fat oxidation is increased in close relationship with plasma free fatty acid availability after combined fasting and repeated incremental exercise tests in healthy highly trained men. Therefore it may be argued that whole body fat oxidation rate measured in most cases after an overnight fast indeed does not represent whole body maximal fat oxidation rate but a whole body peak fat oxidation rate within the context of the preexercise standardization obtained in the study design.

Effect of Short-Term Free Fatty Acids Elevation on Mitochondrial Function in Skeletal Muscle of Healthy Individuals

Mitochondrial dysfunction has been proposed as an underlying mechanism in the pathogenesis of insulin resistance and type 2 diabetes mellitus. To determine whether mitochondrial dysfunction plays a role in the free fatty acid (FFA)-induced impairment in insulin action in skeletal muscle of healthy subjects. Eleven lean normal glucose tolerant individuals received 8 h lipid and saline infusion on separate days with a euglycemic insulin clamp during the last 2 h. Vastus lateralis muscle biopsies were performed at baseline and after 6 h lipid or saline infusion. Inner mitochondrial membrane potential (Psi(m)) and mitochondrial mass were determined ex vivo by confocal microscopy. Compared with saline infusion, lipid infusion reduced whole-body glucose uptake by 22% (P < 0.05). Psi(m) decreased by 33% (P < 0.005) after lipid infusion and the decrement in Psi(m) correlated with change in plasma FFA after lipid infusion (r = 0.753; P < 0.005). Mitochondrial content and morphology did not change after lipid infusion. No significant changes in genes expression, citrate synthase activity, and total ATP content were observed after either lipid or saline infusion. Short-term physiological increase in plasma FFA concentration in lean normal glucose tolerant subjects induces insulin resistance and impairs mitochondrial membrane potential but has no significant effects on mitochondrial content, gene expression, ATP content, or citrate synthase activity.

Free fatty acid kinetics in the late phase of postexercise recovery: importance of resting fatty acid metabolism and exercise-induced energy deficit

Free fatty acid (FFA) availability increases several-fold during exercise and remains significantly elevated for at least 3 to 6 hours after exercise cessation. Little, however, is known regarding the duration of the postexercise rise in FFA flux. In the present study, we used stable isotope–labeled palmitate infusion to examine fatty acid metabolism in 27 healthy untrained men and women (age, 29 ± 7 years; body mass index, 25 ± 4 kg/m2) between 13 to 16 hours and 21 to 24 hours after a single bout of moderate-intensity endurance exercise (1-2 hours at 60% of peak oxygen consumption), performed in the evening, and after a time-matched resting trial. Postabsorptive FFA rate of appearance (Ra) and FFA concentration in plasma were significantly greater after exercise than rest throughout the recovery period (P < .015), but the exercise-induced increases declined from approximately 40% at 13 to 16 hours to approximately 10% at 21 to 24 hours postexercise (P = .001). The magnitude of the exercise-induced increase in plasma FFA concentration was proportional to the increase in FFA Ra. Correlation analysis demonstrated that exercise-induced changes in plasma FFA Ra at 13 to 16 hours are (1) negatively associated with resting plasma FFA Ra and (2) positively associated with the net energy expenditure of exercise and the exercise-induced changes in whole-body fat oxidation rate (all P values < .05). In multivariate stepwise linear regression analysis, baseline plasma FFA Ra (P ≤ .008) and net energy expenditure of exercise (P ≤ .005) independently predicted the exercise-induced change in plasma FFA Ra at 13 to 16 hours. We conclude that the exercise-induced increase in FFA mobilization is (1) long-lived, persisting for 12 to 24 hours after exercise, with a progressive decline with time; (2) greater in subjects with low than high resting plasma FFA availability; and (3) greater after exercise with high than low energy demand.

Exercise-induced Ghrelin Secretion is Associated with Increased Lipolysis

0996 PURPOSE: Ghrelin is a gastrointestinal hormone that has been implicated in signaling increased energy need as a rise in its plasma concentration precedes food intake and occurs after weight loss (Cummings, et al., 2001, 2002). Ghrelin is inhibited by postprandial insulin release (Saad, et al., 2002) and is a growth hormone secretagogue (Kojima, et al., 1999). It is not known whether ghrelin secretion is responsive to increases in energy expenditure due to exercise as exercise intensity sufficient to elicit growth hormone secretion was reported to have no effect on plasma ghrelin (Dall, 2002). Therefore, we hypothesized that (1) exercise-induced increases in energy expenditure will increase ghrelin secretion and (2) exercise during postprandial increases in insulin secretion will suppress ghrelin secretion. METHODS: In this experiment, eight postmenopausal women engaged in moderate intensity exercise in the form of an AM and PM two-hour bout of walking, each producing an expenditure of approximately 400 Kcal and timed before (ExBM) or after (ExAM) two daily weight maintenance meals. We evaluated the effects of fasting and postprandial exercise on plasma ghrelin, insulin, and free fatty acid (FFA) concentrations. Energy expenditure was measured by indirect calorimetry. The increase in plasma FFA concentration was used as a physiological marker of postabsorptive energy need. RESULTS: Plasma ghrelin increased only when exercise was performed in the fasted state (ExBM F = 11.6, p = 0.0019) and not when exercise was performed after the meal. Lipolysis increased by approximately 50% in the ExBM condition compared to the ExAM (F = 11.02, p = 0.0006). There was a significant correlation between ghrelin and FFA concentrations during the diurnal period (0600–2200 hr) in both exercise conditions (ExBM F = 24.12, p = < 0.0001; ExAM F = 10.45, p = 0.0032). CONCLUSIONS: Our results show that ghrelin secretion increases in response to exercise performed in a fasted state. A significant correlation between plasma ghrelin and FFA concentrations suggests that the functional role of ghrelin may be to stimulate lipolysis by way of increased growth hormone secretion.

Intramyocellular lipid content is increased after exercise in nonexercising human skeletal muscle.

Intramyocellular lipid (IMCL) content has been reported to decrease after prolonged submaximal exercise in active muscle and, therefore, seems to form an important local substrate source. Because exercise leads to a substantial increase in plasma free fatty acid (FFA) availability with a concomitant increase in FFA uptake by muscle tissue, we aimed to investigate potential differences in the net changes in IMCL content between contracting and noncontracting skeletal muscle after prolonged endurance exercise. IMCL content was quantified by magnetic resonance spectroscopy in eight trained cyclists before and after a 3-h cycling protocol (55% maximal energy output) in the exercising vastus lateralis and the nonexercising biceps brachii muscle. Blood samples were taken before and after exercise to determine plasma FFA, glycerol, and triglyceride concentrations, and substrate oxidation was measured with indirect calorimetry. Prolonged endurance exercise resulted in a 20.4 +/- 2.8% (P < 0.001) decrease in IMCL content in the vastus lateralis muscle. In contrast, we observed a substantial (37.9 +/- 9.7%; P < 0.01) increase in IMCL content in the less active biceps brachii muscle. Plasma FFA and glycerol concentrations were substantially increased after exercise (from 85 +/- 6 to 1450 +/- 55 and 57 +/- 11 to 474 +/- 54 microM, respectively; P < 0.001), whereas plasma triglyceride concentrations were decreased (from 1498 +/- 39 to 703 +/- 7 microM; P < 0.001). IMCL is an important substrate source during prolonged moderate-intensity exercise and is substantially decreased in the active vastus lateralis muscle. However, prolonged endurance exercise with its concomitant increase in plasma FFA concentration results in a net increase in IMCL content in less active muscle.

Dexamethasone-induced insulin resistance and pancreatic adaptive response in aging rats are not modified by oral vanadyl sulfate treatment.

To explore the adaptive response of the endocrine pancreas in vivo and in vitro and the possible beneficial effect of the insulino-mimetic agent vanadyl sulfate (VOSO(4)), using glucocorticoid treatment to increase insulin resistance, in aging rats. Dexamethasone (Dex) (0.13 mg/kg b.w.) was administered daily for 13 days to 3- and 18-month old Sprague-Dawley rats and oral VOSO(4) was given from the 5th day. Plasma glucose, insulin and free fatty acids (FFA) concentrations were measured during these treatments and the insulin secretory response of the isolated perfused pancreas was assessed at the end of the experiment. In both young and aging rats, particularly in the latter, hyperinsulinemia and increased in vitro insulin responsiveness to glucose were observed in response to Dex treatment, concomitant with an increase in plasma FFA concentrations. Thus, in glucocorticoid-treated animals, the beta-cell adaptive response occurred in both age groups and could possibly be mediated by increased circulating FFA; however, it was insufficient to prevent hyperglycemia in 60% of aging animals. Oral VOSO(4) administration failed to correct Dex-induced alterations in glucose and lipid metabolism, although it influenced in vitro beta-cell responsiveness to stimuli in aging rats.

The effect of an increased free fatty acid concentration on thermogenesis and substrate oxidation in obese and lean men

To examine whether a certain increase in plasma free fatty acid (FFA) concentration leads to similar increases in lipid oxidation and energy expenditure in obese and lean men. The study protocol consisted of a 30 min baseline period after which subjects received an i.v. bolus of 1000 IE heparin. Then consecutive infusions of 4.9, 9.8 and 19.6 microl/kg fat-free mass (FFM).min of a lipid heparin mixture were started, each infusion for 30 min. Eleven obese and 13 lean men with a mean body mass index (BMI) of 34.2+/-1.0 (+/-s.e.m.) and 23.9+/-0.5 kg/m(2) and age 46.0+/-1.0 and 42.6+/-1.5 y, respectively. Energy expenditure, respiratory exchange ratio (RER) and carbohydrate and lipid oxidation were continuously measured by indirect calorimetry. At the end of each infusion period, a blood sample was taken for FFA, glycerol, insulin, beta-hydroxybutyrate, noradrenaline and adrenaline determination. At baseline, plasma FFA levels were comparable in both groups. Lipid heparin infusion increased plasma FFA concentration by 301+/-47 micromol/l and 332+/-27 micromol/l in obese and lean men. Energy expenditure increased similarly in obese and lean men (0.34+/-0.08 vs 0.40+/-0.08 kJ/min, NS) during lipid heparin infusion, whereas RER decreased similarly in both groups. Lipid oxidation rates were comparable at baseline and increased similarly in obese and lean men (19+/-5 vs 13+/-4 mg/min, NS). Baseline plasma insulin levels were higher in the obese, but did not change during lipid heparin infusion. Plasma beta-hydroxybutyrate concentrations were similar at baseline, but increased significantly less in the obese during lipid heparin infusion. Baseline noradrenaline and adrenaline concentrations did not differ significantly between groups. During lipid heparin infusion, plasma noradrenaline levels decreased significantly, but plasma adrenaline levels remained unchanged in both groups. A certain increase in plasma FFA concentration leads to similar increases in lipid oxidation and energy expenditure in obese and lean men. The accumulation of fat in obese subjects may therefore be more likely to be due to a defect in adipose tissue lipolysis than a defect in lipid oxidation. International Journal of Obesity (2001) 25, 33-38

Plasma Free Fatty Acids in Neonates with Congenital Hypothyroidism

Since the introduction of neonatal mass screening for congenital hypothyroidism (CH), numerous cases have been detected. It is of interest that even severely hypothyroid neonates rarely exhibit bradycardia, hypothermia, or inactivity, which have been recognized as typical signs of CH. Regarding neonates and young infants, few reported data are available on the effects of thyroid hormones on energy expenditure. Plasma free fatty acids (FFAs), markers for lipolysis, play essential roles in maintaining physiologic homeostasis. To study fuel utilization in CH neonates, we measured heart rates, plasma FFA, and thyroid hormones before and after levothryoxine (LT4) replacement therapy. Fifty-five screen-detected CH neonates and 29 age-matched normal neonates for controls were enrolled. The CH neonates were divided into two groups according to serum thyroid hormone levels: a mildly hypothyroid group (n = 37), serum thyrotropin (TSH) less than 100 microIU/mL and free thyroxine (FT4) 0.6 ng/dL or more; and a severely hypothyroid group (n = 18), TSH 100 microIU/mL or more and FT4 less than 0.6 ng/dL. Twenty-four of the 55 patients had their heart rates measured by electrocardiography. Fasting blood samples were taken from the subjects during physical movements. Serum levels of TSH, FT4, FFA, and other blood chemicals, measured on an autoanalyzer system in our hospital, were compared before and after LT4 substitution therapy. The following results were obtained. The mean plasma FFA values before LT4 replacement were 208.5 +/- 89.4 microEq/L in the mildly hypothyroid group, 228.5 +/- 114.7 microEq/L in the severely hypothyroid group, and 213.9 +/- 97.7 microEq/L in controls. No statistical differences were noted among the three values. Two months after LT4 replacement therapy, at the age of 3 months, plasma FFA concentrations significantly increased in both groups compared with those before the therapy. Control infants also showed a significant increase in plasma FFA concentrations from 1 to 3 months of age. There were no significant differences in plasma FFA concentrations among the three groups at the age of 3 months. No significant correlations were found between plasma FFA and serum thyroid hormones. From these results it is suggested that in neonates and young infants, thyroid hormones do not play major roles in mobilization of fats through the adrenergic regulation of lipolysis for energy supply. This may be one of the reasons for the unexpectedly mild signs and symptoms in the screen-detected hypothyroid neonates.

Lipid infusion lowers sympathetic nervous activity and leads to increased beta-cell responsiveness to glucose.

We investigated the possible involvement of the autonomic nervous system in the effect of a long-term elevation of plasma free fatty acid (FFA) concentration on glucose-induced insulin secretion (GIIS) in rats. Rats were infused with an emulsion of triglycerides (Intralipid) for 48 hours (IL rats). This resulted in a twofold increase in plasma FFA concentration. At the end of infusion, GIIS as reflected in the insulinogenic index (DeltaI/DeltaG) was 2.5-fold greater in IL rats compared with control saline-infused rats. The ratio of sympathetic to parasympathetic nervous activities was sharply decreased in IL rats relative to controls. GIIS was studied in the presence of increasing amounts of alpha- and beta-adrenoreceptor agonists and antagonists. The lowest concentrations of the alpha2A-adrenoreceptor agonist oxymetazoline, which were ineffective in control rats, reduced GIIS in IL rats. At the dose of 0.3 pmol/kg, GIIS became similar in IL and control rats. The use of beta-adrenoreceptor agonist (isoproterenol) or antagonist (propranolol) did not result in a significant alteration in GIIS in both groups. GIIS remained as high in IL vagotomized rats as in intact IL rats, indicating that changes in parasympathetic tone were of minor importance. Altogether, the data show that lipid infusion provokes beta-cell hyperresponsiveness in vivo, at least in part through changes in alpha2-adrenergic innervation.

Role of insulin resistance in human disease

Resistance to insulin-stimulated glucose uptake is present in the majority of patients with impaired glucose tolerance (IGT) or non-insulin-dependent diabetes mellitus (NIDDM) and in ∼25% of nonobese individuals with normal oral glucose tolerance. In these conditions, deterioration of glucose tolerance can only be prevented if the β-cell is able to increase its insulin secretory response and maintain a state of chronic hyperinsulinemia. When this goal cannot be achieved, gross decompensation of glucose homeostasis occurs. The relationship between insulin resistance, plasma insulin level, and glucose intolerance is mediated to a significant degree by changes in ambient plasma free-fatty acid (FFA) concentration. Patients with NIDDM are also resistant to insulin suppression of plasma FFA concentration, but plasma FFA concentrations can be reduced by relatively small increments in insulin concentration.Consequently, elevations of circulating plasma FFA concentration can be prevented if large amounts of insulin can be secreted. If hyperinsulinemia cannot be maintained, plasma FFA concentration will not be suppressed normally, and the resulting increase in plasma FFA concentration will lead to increased hepatic glucose production. Because these events take place in individuals who are quite resistant to insulinstimulated glucose uptake, it is apparent that even small increases in hepatic glucose production are likely to lead to significant fasting hyperglycemia under these conditions. Although hyperinsulinemia may prevent frank decompensation of glucose homeostasis in insulin-resistant individuals, this compensatory response of the endocrine pancreas is not without its price. Patients with hypertension, treated or untreated, are insulin resistant, hyperglycemic, and hyperinsulinemic. In addition, a direct relationship between plasma insulin concentration and blood pressure has been noted. Hypertension can also be produced in normal rats when they are fed a fructose-enriched diet, an intervention that also leads to the development of insulin resistance and hyperinsulinemia. The development of hypertension in normal rats by an experimental manipulation known to induce insulin resistance and hyperinsulinemia provides further support for the view that the relationship between the three variables may be a causal one. However, even if insulin resistance and hyperinsulinemia are not involved in the etiology of hypertension, it is likely that the increased risk of coronary artery disease (CAD) in patients with hypertension and the fact that this risk if not reduced with antihypertensive treatment are due to the clustering of risk factors for CAD, in addition to high blood pressure, associated with insulin resistance. These include hyperinsulinemia, IGT, increased plasma triglyceride concentration, and decreased high-density lipoprotein cholesterol concentration, all of which are associated with increased risk for CAD. It is likely that the same risk factors play a significant role in the genesis of CAD in the population as a whole. Based on these considerations the possibility is raised that resistance to insulin-stimulated glucose uptake and hyperinsulinemia are involved in the etiology and clinical course of three major related diseases— NIDDM, hypertension, and CAD.

Effects of a 48-h Fat Infusion on Insulin Secretion and Glucose Utilization

To determine the effects of prolonged elevation of plasma free fatty acids (FFAs) on insulin secretion, we infused Liposyn II (4.3 mumol.kg-1.min-1) plus heparin (0.4 U.kg-1.min-1) intravenously into six healthy volunteers for 48 h. Another six volunteers received saline infusions and served as control subjects. In all 12 subjects (11 men and 1 woman), plasma glucose was clamped at approximately 8.6 mmol/l. Liposyn/heparin infusion resulted in a 9.4-fold increase in plasma FFA concentration (from 132 to 1,237 mumol/l), a 46% increase in insulin secretion rates (from 241 to 352 pmol/min, P < 0.05) (determined by deconvolution of plasma C-peptide concentration), and a 30% decrease, during the initial 24 h, in the rate of glucose infusion needed to maintain hyperglycemia (from 55.5 to 39.1 mumol.kg-1.min-1, P < 0.02). This decrease disappeared during the second 24 h. In summary, we found that physiologically elevated plasma FFAs 1) potentiated glucose-stimulated insulin secretion for 48 h and 2) initially caused peripheral insulin resistance that disappeared during the 2nd day, probably as a result of elevated circulating insulin levels. We conclude that in healthy volunteers under hyperglycemic conditions, fat infusion produced insulin resistance that was compensated for after approximately 24 h by persistent hypersecretion of insulin.

Effect of insulin on oxidative and nonoxidative pathways of free fatty acid metabolism in human obesity.

The dose-response relationship between the plasma insulin concentration and oxidative and nonoxidative pathways of free fatty acid (FFA) metabolism was examined in 11 obese and 7 lean subjects using a stepwise insulin clamp technique in combination with indirect calorimetry and infusion of [1-14C]palmitate. The fasting plasma FFA concentration was elevated in obese subjects (793 +/- 43 vs. 642 +/- 39 mumol/l; P less than 0.01) and was associated with an increased basal rate of plasma FFA turnover, FFA oxidation, and nonoxidative FFA disposal, i.e., reesterification (all P less than 0.01). Suppression of plasma FFA turnover by physiological increments in plasma insulin was impaired in obese compared with lean subjects. However, plasma FFA turnover expressed per kilogram fat mass was normally suppressed by insulin in obese subjects. Although insulin suppressed plasma FFA oxidation to the same extent in lean and obese subjects, inhibition of total lipid oxidation by insulin was impaired in the obese group. Obese subjects had an enhanced basal rate of nonoxidative FFA disposal, which was suppressed less by physiological increments in plasma insulin compared with lean controls. Therefore, we conclude that 1) lipolysis in uncomplicated obesity is normally sensitive to insulin; the enhanced FFA flux is simply a consequence of the increased fat mass. 2) Nonoxidative FFA disposal expressed per lean body mass is enhanced in obese subjects and correlates with the increase in plasma FFA concentration and fat mass. 3) Enhanced oxidation of intracellular lipids contributes to the enhanced rate of total lipid oxidation in obese subjects.

Changes in Plasma Catecholamine, Free Fatty Acid, and Glucose Concentrations, and Plasma Monoamine Oxidase Activity Before and After Feeding in Laying Hens

In order to better understand the relationship of free fatty acid (FFA) concentrations to feed intake in laying hens, plasma levels of catecholamine, glucose, and FFA and plasma monoamine oxidase activity were measured. Blood samples were taken in the morning before and after the start of feeding via chronic brachial vein catheters. Plasma concentrations of epinephrine and norepinephrine were analyzed by modified HPLC with an electrochemical detection method. Plasma concentrations of FFA and glucose were not significantly different before and after the start of feeding, however a negative correlation (r = −.763, r2 = .582, P < .01) between these parameters was observed. No significant correlations between the plasma concentration of FFA and plasma concentrations of epinephrine or norepinephrine before and after the start of feeding were observed. However these were significantly correlated (r = .444, r2 = .197, P < .05 for FFA and epinephrine; r = .787, r2 = .619, P < .01 for FFA and norepinephrine) when the behavioral activity of hens was low, such as in resting or feeding. Plasma activity of monoamine oxidase was not different before and after the start of feeding, and no relationship was observed between plasma monoamine oxidase activity and plasma epinephrine or norepinephrine concentration. It is suggested that the increase in plasma FFA concentration before feeding would be elicited by the increase in the circulating epinephrine and norepinephrine concentrations. Plasma FFA concentration was not affected by the increase in circulating epinephrine and norepinephrine concentrations during active behavior such as pacing and egg call before and after oviposition.

Banting lecture 1988. Role of insulin resistance in human disease.

Resistance to insulin-stimulated glucose uptake is present in the majority of patients with impaired glucose tolerance (IGT) or non-insulin-dependent diabetes mellitus (NIDDM) and in approximately 25% of nonobese individuals with normal oral glucose tolerance. In these conditions, deterioration of glucose tolerance can only be prevented if the beta-cell is able to increase its insulin secretory response and maintain a state of chronic hyperinsulinemia. When this goal cannot be achieved, gross decompensation of glucose homeostasis occurs. The relationship between insulin resistance, plasma insulin level, and glucose intolerance is mediated to a significant degree by changes in ambient plasma free-fatty acid (FFA) concentration. Patients with NIDDM are also resistant to insulin suppression of plasma FFA concentration, but plasma FFA concentrations can be reduced by relatively small increments in insulin concentration. Consequently, elevations of circulating plasma FFA concentration can be prevented if large amounts of insulin can be secreted. If hyperinsulinemia cannot be maintained, plasma FFA concentration will not be suppressed normally, and the resulting increase in plasma FFA concentration will lead to increased hepatic glucose production. Because these events take place in individuals who are quite resistant to insulin-stimulated glucose uptake, it is apparent that even small increases in hepatic glucose production are likely to lead to significant fasting hyperglycemia under these conditions. Although hyperinsulinemia may prevent frank decompensation of glucose homeostasis in insulin-resistant individuals, this compensatory response of the endocrine pancreas is not without its price. Patients with hypertension, treated or untreated, are insulin resistant, hyperglycemic, and hyperinsulinemic. In addition, a direct relationship between plasma insulin concentration and blood pressure has been noted. Hypertension can also be produced in normal rats when they are fed a fructose-enriched diet, an intervention that also leads to the development of insulin resistance and hyperinsulinemia. The development of hypertension in normal rats by an experimental manipulation known to induce insulin resistance and hyperinsulinemia provides further support for the view that the relationship between the three variables may be a causal one.(ABSTRACT TRUNCATED AT 400 WORDS)

Plasma Free Fatty Acid Profile in Male and Female Domestic Fowl at Rest and After Exercise

The concentration and profile of the plasma free fatty acid (FFA) pool was determined in three male and three female domestic fowl before and after a 70 min treadmill run. The fatty acid profile of total food lipids was also determined.At rest, palmitic, stearic, oleic, and linoleic acids were the main individual fatty acids in the plasma FFA pool and together constituted 50 to 60% of the total. Shorter chain fatty acids (C10 to C15) made up 24 to 38% of the total. In food lipids C16 and C18 fatty acids constituted more than 95% of total fatty acids, therefore food was not a significant direct source of short chain (<C16) fatty acids.After exercise, there was an 8 to 10 fold increase in plasma FFA concentration. The proportion of lower chain (<C16) FFA decreased and the proportion of C16 and C18 FFA, in particular oleic acid, increased. At the end of exercise the profile of the plasma FFA pool was similar to that of the adipose tissue triglyceride. Release of fatty acids from adipose tissue may be a major influence on exercise-induced changes in the plasma FFA profile.

Bilateral lesions of the SCN abolish lipolytic and hyperphagic responses to 2DG

The effects of intracranial injection of 2-deoxy- D-glucose (2DG) on the plasma free fatty acid (FFA) concentration and food intake in the light (11:00 hr) and dark (23:00 hr) period were examined in male Wistar rats under a 12-hr light (08:00–20:00) and 12-hr dark (20:00–08:00) cycle. In sham-operated rats 2DG injection induced increase in plasma FFA concentration and in food intake in the light period, but not in the dark period. Bilateral lesions of the suprachiasmatic nucleus (SCN) resulted in complete loss of the lipolytic and feeding responses to 2DG in the light period. From these findings it is concluded that the lipolytic and feeding responses to 2DG are photoperiodic and that the SCN is involved in these phenomena.

The effect of cortisol on the metabolic actions of insulin in the echidna, Tachyglossus aculeatus (Shaw)

The effects of insulin on plasma concentrations of glucose, free fatty acids (FFA), amino acids and urea were investigated in saline- and cortisol-treated echidnas ( Tachyglossus aculeatus). Intravenous injection of 0.02 or 0.2 IU of regular insulin/kg in saline-injected echidnas was followed by dose-related decreases in plasma glucose, amino acid and urea concentrations. However, following a rapid decrease to 52 ± 10% of the control value, plasma FFA then increased slowly to a maximum of 254±35%, 8 hr after the injection of 0.2 IU of insulin/kg. An increase in plasma corticosteroid concentration was not observed. Pretreatment with five daily im injections of 0.2 mg of cortisol acetate/kg did not affect the early hypoglycemic and lipogenic actions of insulin but decreased its effect on plasma amino acid and urea concentrations. The later increase in plasma FFA concentration was abolished. It is concluded that insulin has potent actions on carbohydrate, protein, and fat metabolism in the echidna and that antagonistic effects of the glucocorticoids on these actions are minimal.

D-Galactosamine hepatotoxicity : V. Role of free fatty acids in the pathogenesis of fatty liver

The role of free fatty acids (FFA) in the pathogenesis of fatty liver was investigated in female rats who received a single ip injection of d-galactosamine-HCl, (GalN), 750 mg/kg body weight. Groups of rats were either fasted for 14 hr prior to GalN injection and then fasted for the duration of the experiment or were fed ad libitum prior to and after GalN administration. Plasma FFA were determined in groups of fasting or fed rats sacrificed at intervals between 0 and 24 hr after GalN administration. The results revealed a progressive increase in plasma FFA in GalN-injected fasted rats (0 hr, 0.40 μmol/ml; 24 hr, 1.09 μmol/ml) whereas in fed animals only a modest increase in plasma FFA concentrations occurred. Hepatic triglyceride content was determined in groups of fasted and fed rats at 6 and 24 hr after GalN administration. Hepatic triglycerides, in fasted rats, were increased 7-fold at 6 hr (22.4 ± 8.5 mg/g) and were markedly increased at 24 hr (114.8 ± 18.4 mg/g). In contrast, feeding protected the rats from the development of fatty liver since hepatic triglycerides were only twice controls at 6 hr and 4-fold increased 24 hr after GalN. Ultrastructural studies were performed at 15, 24, and 48 hr after GalN in fed and fasted rats. Electron microscopy disclosed hepatocellular necrosis and profound fat accumulation in the fasted animals; however, feeding afforded marked protection against the development of fatty liver and hepatic injury. The results of these studies indicate that the GalN-induced fatty liver is associated with a sustained elevation of plasma FFA. The increase in plasma FFA can be prevented by feeding the animals prior to and after GalN administration suggesting that a stimulus for FFA elevation may be the alterations in carbohydrate metabolism known to be induced by GalN in rat liver.

Diphenylhydantoin Binding to Proteins in Plasma and Its Dependence on Free Fatty Acid and Bilirubin Concentration in Dogs and Newborn Infants

Extract: The binding of diphenylhydantoin (DPH) to plasma proteins was studied with an equilibrium dialysis method in plasmas in which concentrations of free fatty acids (FFA) were varied by physiologic means. In blood-perfused dog subcutaneous adipose tissue, sympathetic nerve stimulation caused an increase in plasma FFA concentration from control values of 0.26–0.58 mM to peak levels of 0.63 to 3.44 mM. There was a linear relation between the binding of DPH and the FFA concentration in plasma from the same dog. When rat epididymal adipose tissue was incubated in dog plasma containing DPH, DPH protein binding decreased and tissue binding of the drug increased with increasing lipolytic rate. In plasma from 42 newborn infants the degree of DPH binding was significantly related to the albumin concentration as well as the bilirubin to albumin and FFA to albumin concentration ratios. Speculation: Our data indicate that physiologically occurring variations in plasma FFA concentration can alter the plasma protein binding of drugs. We propose that such displacement will be quantitatively most important in blood perfusing adipose tissue during lipolysis and that the effect might lead to a preferential distribution of the drug to fat tissue during lipolysis.